The key role of vitamin D (vit D) in maintaining optimal bone health has long been recognized, but its role in modulating the innate immune response and inflammatory reaction has only recently come under active investigation. As such, vit D is an increasingly frequently chosen and prescribed high dose dietary supplement, because it is thought to improve immune and inflammatory status in healthy people of all ages, and in those with chronic diseases including HIV/AIDS. Vit D also has calciotrophic functions essential for bone health, and poor vit D status contributes to the osteopenia/osteoporosis associated with antiretroviral therapy (ART). Vit D may improve insulin/glucose/lipid metabolism, blood pressure, and risk of some cancers, all of which may complicate HIV/AIDS and its treatments. Poor vit D status is common in HIV/AIDS patients of all ages and factors such as age, skin pigment, lactose intolerance, and sun exposure alter the risks for vit D deficiency. In the multicenter U.S. REACH study of adolescents (72% African American), with and without HIV, showed that 87% had low serum 25-hydroxyvitamin D3 (25D) concentrations (<15 ng/mL), compared to 34% in a recent sample of healthy African American children from Philadelphia. Young African Americans are disproportionately affected by HIV infection in the US (~ 55% among persons with HIV aged 13 to 24 years are African American), and are also at high risk for vit D deficiency. Vit D therapy has great promise to improve major medical conditions and the quality of life for our HIV/AIDS patients, yet the potential role of vitamin D in the treatment of HIV/AIDS has not been formally tested. Well-designed randomized trials are urgently needed to determine vit D supplementation safety and efficacy. The investigators propose a two-phase study to establish safety and efficacy of high dose vit D supplementation in children and adults with HIV/AIDS. In Study Phase I, the safety and efficacy of two oral vit D3 doses (4000 and 7000 IU/d) are determined over 12 weeks in 44 subjects ages 5.0 to 24.9 years. The key safety measure is concurrently elevated serum calcium and 25D concentrations. Efficacy is evaluated by serum 25D concentration and cathelicidin (innate immune, antimicrobial protein) mRNA expression. Study Phase II is a 12 month, double blind, randomized, placebo controlled supplementation study (n=52). Key outcomes include safety and long- term 25D concentration within the goal range (32 to 160 ng/mL), improved cathecidin mRNA expression, and measures of bone, muscle, inflammation, growth and body composition status, and HIV/AIDS disease severity. Based on the evidence and promise, vit D clearly deserves to be among the first nutrients evaluated in the National Center for Complimentary and Alternative Medicine (NCCAM) HIV research program. PUBLIC HEALTH RELEVANCE: Optimal vitamin D concentration and metabolism are essential for normal immune function, growth, muscle, bone, and inflammatory status in children, adolescents and adults with HIV/AIDS. The impact of vitamin D supplementation will be evaluated for safety and efficacy using clinically important outcomes, and this will overcome the critical barrier for use of vitamin D supplementation in research and clinical care. Inexpensive and easy to administer, vitamin D supplementation may prove to be an effective and feasible treatment for symptoms and prevention of side effects for people of all ages living with HIV/AIDS in the US and around the world.